|Year : 2019 | Volume
| Issue : 1 | Page : 81-91
Cell-based treatment strategies for intervertebral disc degeneration: An overview on potentials and shortcomings
Prasanthi Sampara, Rajkiran Reddy Banala, Satish Kumar Vemurit, AV Gurava Reddy, G P V Subbaiah
Sunshine Medical Academy for Research and Training, Sunshine Hospitals, Secunderabad, Telangana, India
|Date of Web Publication||11-Jan-2019|
Dr. G P V Subbaiah
Sunshine Medical Academy for Research and Training, Sunshine Hospitals, Secunderabad - 500 003, Telangana
Source of Support: None, Conflict of Interest: None
The intervertebral discs (IVDs) are the cushioning pads of fibrocartilage, which are immeasurably vital for the uprightness of vertebral column and for its function. IVD provides flexibility, tensile strength to the spine, and also cope up with varied types of biomechanical stresses. IVD degeneration (IVDD) is one of the musculoskeletal disorders mostly seen in older population, and it is the foremost cause of low back pain and consequences of IVDD are disc herniation, spinal stenosis, and degenerative lumbar scoliosis. Yet the therapeutic options are restricted and the treatments given remain unsatisfactory putting more economical burden on world's population. IVDD is considered as a multifactorial disorder, due to the involvement of factors such as genetic inheritance, alterations in cellular composition, and anabolic and catabolic reactions, which could initiate degenerative process in the IVD. However, our conception on IVD genesis and the etiopathology of IVDD have given us an opportunity for exploring and formulate appropriate therapies to tackle IVDD. The cell therapy gives scope for sustained matrix synthesis, controlled inflammation, and prevention of osteophyte formation in IVD. The present review focuses on the existing issues related to current therapeutic approaches and about latest evidence on cell therapy-based regeneration of IVD and maintaining the microenvironment of cellular matrix which holds a promise for future therapeutic applications.
Keywords: Cell therapy, cellular matrix, intervertebral disc degeneration, nucleus pulposus, stem cells
|How to cite this article:|
Sampara P, Banala RR, Vemurit SK, Gurava Reddy A V, Subbaiah G P. Cell-based treatment strategies for intervertebral disc degeneration: An overview on potentials and shortcomings. Indian Spine J 2019;2:81-91
|How to cite this URL:|
Sampara P, Banala RR, Vemurit SK, Gurava Reddy A V, Subbaiah G P. Cell-based treatment strategies for intervertebral disc degeneration: An overview on potentials and shortcomings. Indian Spine J [serial online] 2019 [cited 2019 Nov 18];2:81-91. Available from: http://www.isjonline.com/text.asp?2019/2/1/81/249894
Prasanthi Sampara, Rajkiran Reddy Banala, Satish Kumar Vemurit: Indicates equal authorship
| Introduction|| |
Intervertebral disc degeneration (IVDD) is a multifaceted chronic process with cell-mediated response toward alterations in the cellular microenvironment within the disc causing progressive loss of proteoglycans and water content in the nucleus pulposus (NP) and annulus fibrosus (AF), thereby causing progressive structural failure. IVDD is a major cause of low back pain and as such is a significant health problem. A study done by Pellisé et al. estimated that 84% of the world population experiences low back pain at some point in their lifetime. According to a study published in Lancet (2012), on Global Burden of Disease, it is estimated that 632 million people worldwide are affected by low back pain.
The IVD is a complex fibrocartilaginous structure that provides mechanical support and flexibility to the vertebral column. The IVD is made up of three distinct components; the NP is the central gelatinous layer and it consists of proteoglycans, predominantly aggrecan and collagen Type II. The second component AF is highly organized and consists of collagen Type I fibers. The third component is the cartilaginous endplates (CEPs) consisting of hyaline cartilage that facilitates the diffusion of nutrients and oxygen to the avascular internal structure of IVD. [Figure 1] illustrates characteristics of a healthy disc and a degenerated disc. The healthy discs maintain a balance between anabolic and catabolic processes, whereas the imbalance between the synthesis and catabolism of the extracellular matrix (ECM) components may contribute to the IVDD. This imbalance between the catabolic and anabolic processes results in the loss of proteoglycans and water content in the NP and finally contributes to the degeneration of the IVD. When a healthy IVD is compared to the degenerated IVD, it is observed that the degenerated IVD has inflated inflammation, innervation and angiogenesis, the boundary between the NP and AF is damaged, and the extension of the interlamellar space comprises of collagen bundles surrounded by the AF that usually cause disc bulging. The effects of the degenerative cascade are inflammation, cartilage endplate-calcified osteophyte formation in the adjacent vertebral bone, derangement and delamination of AF, and in-growth of pain nerves and blood vessels into a typically aneural and avascular tissue. Hence, the reinforcement of cells from the surrounding environment to augment the supply of viable and functioning cells is an aspect of regenerative process of an organ.
|Figure 1: A comparative profile of the healthy and degenerative disc. Various morphological changes and structural changes such as disc bulging, blood vessel in growth, cartilaginous endplate calcification, and loss of the boundaries can be observed in the degenerative intervertebral disc when compared to the healthy disc|
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The IVDD is thought to initiate in the NP where there is loss of normal matrix and increased matrix metalloproteinase (MMP) production which is responsible for the catabolic activity. As the degeneration of IVD advances within the NP cells, the collagen Type II is progressively substituted by more fibrous collagen Type I, and therefore, the overall proteoglycan composition of the NP is abridged and changed by decreased synthesis of aggrecan, thereby leading to decreased hydration of the ECM within the NP. At the same time, the matrix degradation is stimulated by the upregulation of MMPs and a disintegrin and metalloproteinase with thrombospondin motifs. The structural changes within the ECM throughout the degeneration of IVD are also associated with the cellular changes such as increased cell apoptosis and cell senescence. The activation of apoptotic pathways and cell senescence is believed to be having major impact in IVDD [Figure 2].
|Figure 2: The changes are involved in the intervertebral disc degeneration: The changes include structural changes, cellular changes, genetic variations, and the dysregulation of inflammatory mediators and cytokines|
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The current treatment modalities for IVDD include pain medications, physical therapy, epidural steroid injections, nucleotomy, spinal fusion, and disc replacement. The efficacy and long-term outcomes of these surgical and nonsurgical treatments are neither predictable nor reliable as they mainly focus on symptomatic relief with no clinical therapy targeting the reversal of disc degeneration. Recent progress in tissue engineering and regenerative medicine has increased the interest in developing a biological approach to this condition through which cells alone or together with biomaterials would be implanted into the NP to both repopulate and stimulate native cells to produce a healthier ECM. In this article, we review the current understanding of the pathogenesis of IVDD and discuss the cell-based treatment strategies based on the cellular and molecular features of the IVD. The cell therapy can be done using biomaterials and cells either individually or in combination for the regeneration of IVD.
Cell therapy designates the most recent phase of revolution in the field of regenerative medicine and biotechnology. Cell therapies offer an assurance of treating and changing the diseases that cannot be addressed efficiently by the predominant treatments. The main objective of cell therapy is to repair the mechanisms underlying disease initiation and progression and achieved through trophic effect or by cell replacement. Cell therapy uses various cell types, such as stem cells, progenitor cells, or primary cells that can be either directly transplanted into the affected region or recruited from the patient's own tissues to stimulate self-repair. There are two major mechanisms of action that are involved in cell therapies. One is based on the replacement of injured cells or tissue by engraftment into the damaged tissue and the second mechanism is based on the stimulation of endogenous tissue self-healing processes through trophic effects mediated by cytokine and growth factor secretion. Currently, cell therapies are being used in the treatment of many neurologic, cardiac, and orthopedic diseases. Research is still being done on the use of cell therapies in IVD. Cell therapies for IVD regeneration currently depend on the transplantation of IVD cells or stem cells directly into the affected site on the degenerated disc.
| Materials and Methods|| |
We conducted an electronic search for research articles published only in English in the area of IVDD and cell therapies strategies using particular keywords such as IVDD and cell therapies, tissue engineering and intervertebral disc, regeneration of disc, and stem cells or progenitors. We have limited ourselves from considering published materials which were older than 20 years. During our search, we have come across various types of articles including original research, reviews, and also clinical trial information from databases of NHS evidence, TRIP, Cochrane systemic, PubMed, etc. Our focus was mainly on the employment of stem cells and disc cells such as NP, AF, and chondrocytes taken from autologous and heterologous source in treatment and regeneration of disc with limited side effects or with chances of sustaining for long time.
Cell-based therapy is the optimal treatment strategy in mid-stage degeneration because it directly addresses the decreased number of viable chondrocytes and disc cells within the diseased disc space. In the past decade, cellular therapy has gained significant attention for addressing the regeneration of the disc by controlling cell loss and proteoglycans components. Cell-based therapy can be performed using different types of differentiated cells, such as NP cells, AF cells, cartilaginous chondrocytes, and progenitor cells. The choice of the cells depends on certain practical issues such as accessibility, abundance, and safety concerns that include tumorigenesis and immunogenicity. The avascular nature of the IVD creates an acidic, hypertonic, hypoglycemic, and hypoxic microenvironment forming a barrier for exogenous cells to survive. Therefore, in cell-based therapy, choosing a cell source is essential for the successful outcome of the regeneration of the IVD as the implanted cells need to be able to survive and produce tissue of the desired quantity. The abundant animal studies conducted till date include the use of stem cells and IVD cells which are taken from autologous, allogeneic, and xenogeneic sources. Autologous cells are considered to be ideal as they can overcome the concerns over disease transmission and immune responses and these cells harvested from bone marrow and adipose tissue can be used for therapy. Allogeneic cells are ideal as they have higher expansion potential than most autologous cells and could be isolated from umbilical cord blood, umbilical tissue, or articular surface. Xenogeneic cells have only been tested in animal models; most of these studies used various human cells to repair injured animal IVDs.
Autologous disc cell and articular chondrocytes transplantation
Tissue-specific cells are in principle the ideal cell types for cell-based therapy and were first to be studied. The implantation of differentiated chondrocytes into the disc will produce proteoglycan and collagen Type I and II under nutrient stress and hypoxia, and meet the cellular demands of the disc. In 2003, a preclinical study was conducted in a canine model by Ganey et al., and it is established that NP disc chondrocyte implantation contributed to ECM regeneration and decelerated disc degeneration. Cell transplantation is an appropriate approach for the regeneration of IVD because of its distinctive organization and structure as the NP is enclosed by the AF and the CEP, which prevents cell migration and permits room for the donor cells to transform. Cell transplantation can increase both the amount of viable cells and accumulation of matrix components. The NP cells have been reported to express Fas ligand which is immune privileged, and thus, some studies considered that the ideal cell candidate for regeneration of IVD may be the disc cells themselves., The use of autologous disc cells is an unconventional approach to repair damaged and chronically inflamed tissue by addressing numerous propagators of degeneration simultaneously. To compare the safety and efficacy of the autologous disc chondrocyte transplantation (ADCT), the first study of ADCT was conducted in a large group of enrolled patients from 2002 to 2006 in a multicenter prospective, randomized, controlled, nonblinded study.
Meisel et al. conducted a study where the patients who received an injection of autologous disc cells showed a reduced amount of fluid content and better pain relief at 24 months when compared with the control group. Nomura et al. (2001) reported that allogeneic rabbits IVD cells slowed down degeneration in a needle puncture model of rabbits IVDD. In a study done by Hohaus et al., the autologous disc cells were implanted in degenerative discs of dogs and they remained viable, produced matrix components such as normal discs, and also retained the disc height. On the basis of the findings, the researchers introduced autologous disc cells in humans following microdiscectomy which is a microdecompression spine surgery, and when compared with the control group at 2 years, the patients showed an increase in the fluid content and pain relief. Gruber et al. conducted studies on the autologous disc cells from sand rats which were expanded in vitro and demonstrated spindle-shaped morphology in the AF and chondrocyte phenotype in NP after transplantation. In 2015, Zhang et al. injected articular chondrocytes into the degenerative disc of rabbits and the study demonstrated the survival of the cells for at least 8 weeks with suppressed inflammation, but the ECM did not resemble the normal NP phenotype. However promising, there are several drawbacks in disk cell transplantation: (1) donor-site morbidity; (2) difficulty expanding cells in vitro while maintaining cell phenotype; (3) scarcity of allograft donor tissue; and (4) issues of immunocompatibility and disease transmission.
The cultured articular chondrocytes are deep-rooted non-disc cell source in the field of regenerative medicine. The extraction of articular chondrocytes is simple as they are from nonweight-bearing parts of the knee and they have the capability to produce NP-like ECM when transplanted in vivo that makes the autologous or allogenic articular chondrocytes a safe and feasible cell source in IVD regeneration. Several in vitro and in vivo studies done using articular chondrocytes injection into degenerated discs of rabbits and porcine models showed promising results.
Stem cell therapy
Stem cell therapies are gaining attention in many neurologic, cardiac, blood diseases and IVDD is no exception. Stem cells are undifferentiated, multipotent cells mainly residing in the bone marrow but also found in many other tissues which are highly accessible and have ability to self-renew, proliferate, and differentiate into multiple mature cell lineages including chondrocytes, and they possess immunomodulatory properties. Stem cells, particularly adult mesenchymal stem cells (MSCs), have been proposed as good alternative and attractive cell choice for regeneration of the IVD as they can be extracted from a variety of adult tissues.
The adult stem cells used in the IVD regeneration include bone marrow-derived MSCs, adipose tissue-derived stem cells, muscle-derived stem cells, hematopoietic stem cells, olfactory membrane stem cells, and synovial stem cells. Adult stem cell types are committed to differentiate into the following lineage of mesenchymal tissues including bone, cartilage, fat, and muscle.
Risbud et al. demonstrated the ability of MSCs differentiating into NP cells when cultured in chondrogenic-culturing conditions; hence, this culture condition can be used as a preconditioning strategy before MSCs implantation into the IVD. Many studies suggested that the regenerative potential of MSCs may be due to the interactions with NP cells and MSCs, and hence, co-culturing system is considered as a powerful tool for investigating the potential of MSC in IVD regeneration. To investigate the compatibility of MSCs in IVD, they are co-cultured with disc cells or tissues in vitro either indirectly or in micromass cultures. A study done by Wei et al. demonstrated the differentiation of rat bone marrow mesenchymal stromal or stem cells (BM-MSCs) into NP-like cells after they were co-cultured with intact IVD tissue in a transwell membrane system where the MSCs were separated from the disc tissue by an insert semipermeable membrane; they demonstrated morphological cell–cell/cell–tissue interactions via the pores through cytoplasmic process. Similar observations were reported in several other studies, which co-cultured MSCs and NP cells under different conditions. Many preclinical studies were conducted using NP cells and MSCs in various animal models [Table 1] and [Figure 3].
|Table 1: Preclinical studies conducted till date using various animal models|
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|Figure 3: Stem cell-based therapy and intervertebral disc regeneration: The figure depicts the steps involved in the stem cell therapy. Stem cells are first isolated and then combined with hydrogels or therapeutic target genes and then injected into the NP of the injured IVD potentially leading to intervertebral disc regeneration|
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Sakai et al. studied the transplantation of bone marrow mesenchymal stromal or stem cells (BMSCs) in a rabbit IVDD model and reported that the cells differentiated into NP-like cells with increased proteoglycan content in the disc. In 2015, Cao et al. co-cultured BM-MSCs with NP cells of the rabbits and demonstrated the upregulation in aggrecan, collagen 2, and SOX 9 expression with an anabolic effect on the NP ECM. Elabd et al. injected autologous hypoxia-cultured BM-MSCs into the IVDs of five patients suffering from low back pain and reported that improvement was seen in a small number after 5 years of injection.
Stem cell therapy is associated with many risks and obstacles such as growth of osteophytes in the spinal canal caused by cell leakage and disc infection and tumorigenesis caused by the multipotent nature of stem cells. To mitigate the risk of cell leakage, various biocompatible cell carriers are developed which would provide three-dimensional (3D) structural framework for MSCs to proliferate and changes in physical characteristics once injected so that it would not leak back into the spinal canal. Successful transplantation of MSCs alone or in conjunction with cell carriers in animal-degenerated IVD models showed survival of chondrocyte-like cells, capable of aggrecan production, and increase in disc height.
Stem cell therapy and tissue engineering approaches
In the advanced stages of IVDD, when the cell death and loss of disc tissue are profound, there is a necessity of complex tissue engineering; thus, a multifunctional therapeutic modality has been derived which is to implant an ex vivo engineered tissue block directly into the degenerated IVD. The idea of an additional cell matrix or a scaffold was initiated in order to facilitate the delivery, orientation, differentiation, growth, replication of cells and also in the cellular metabolism, and constant viability. Scaffolds or matrices are artificial 3D frame structures that mimic the ECM, allowing cellular adhesion, migration, and proliferation and therefore playing a cooperative role in tissue regeneration. The materials with desirable viscoelastic properties are often biodegradable; thus, their function may not be sustained in the long term.
Scaffold is a significant factor in the construction and production of engineered disc tissue. Although synthetic scaffolds are those whose mechanical properties match those of the NP, many naturally occurring biopolymers are preferred as they have an advantage of mimicking the extracellular environment regarding mechanical, permeability, and biochemical properties, therefore providing a bioresorbable temporary 3D microenvironment. The ideal scaffold for tissue repair should respond to important criteria that include (a) manufacturing feasibility; (b) mechanical properties to allow short-term function without affecting long-term function of the tissue; (c) low toxicity of degradation products, in terms of both local tissue response and systemic response; and (d) drug delivery compatibility. The naturally occurring biopolymers can be used alone or in combination as hydrogel scaffolds for both in vitro and in vivo MSC preparation and treatment. A study done by Betram et al., 2005 compared the intradiscal injection of cells suspended in medium and in an injectable fibrin matrix, where rapid loss of cells was observed when injected with medium but the fibrin matrix maintained the injected cells in the NP as fibrin matrix could polymerize after the injection.
Hydrogel scaffolds have been frequently used in tissue engineering, with the objective of maintaining the newly deposited proteoglycan to facilitate the establishment of hydrostatic pressure in the NP. Even though numerous studies have been reported and acknowledged on the efficiency and efficacy of various hydrogel-based scaffolds which are either constructed from natural hydrophilic biomolecules or synthetic polymers, one of the most frequently accepted hydrogel scaffolds for the culturing of NP cells is alginate due to its ease of management, biodegradability, and inert bioactivities.,
Current research in the field of bioengineering in NP cells has attempted to use injectable scaffolds as carriers to deliver cells with the aim of salvaging disc degeneration or as fillings for NP replacement using a minimally invasive approach. Biomaterials such as atelocollagen form a fibrous meshwork as they can self-crosslink. Hyaluronan and chitosan when adapted and modified with cross-linkable moieties are capable of chain polymerization through photochemical reactions. These materials, as injectable media, may deliver cells of interest by providing a transient framework that prevents leakage of implants and allows the growth of the ECM deposited by the introduced cells. The preclinical studies using various bio-scaffolds in tissue engineering are summarized in [Table 2].
The literature review has given us an understanding in regard to the varied cell types and scaffolds used and outcomes in the area of IVDD. Based on the outcomes reported till date, it is only indicating that the effectiveness of cell therapy in tissue engineering could be a putative mode of treatment for addressing the IVDD effectively in the near future [Figure 4].
|Figure 4: Classification of the various biomaterials used in the tissue engineering strategies for the treatment of intervertebral disc degeneration|
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The transplantation of MSCs for the treatment of IVDD in human clinical trials has shown encouraging outcomes. As of November 2016, a total of eight published and 12 unpublished clinical trials assessing cellular transplantation for IVD regeneration were identified. Autologous and allogeneic cells have been used in clinical trials, but xenogeneic cells have only been used in animal studies. The information presented in [Table 3] has been collected from the clinical trials registry database.
|Table 3: Ongoing clinical studies on intervertebral discs regeneration using cell therapy|
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The groups of scientists representing a scientific consortium known as EuroDISC have published their finding and insights on IVDD and its treatment strategies. Scientists employed hematopoietic precursor stem cells (HSCs), MSCs and chondrocytes collected from autologous source and transplanted into the patients to assess the efficiency of HSCs, MSCs, and chondrocytes in the patients enrolled for the clinical trials. The study done by Haufe and Mork reported that the 10 patients who underwent transplantation of autologous HSCs into discs did neither yield any encouraging results nor reduced the low back pain; hence, 80% of the patients opted for surgery. The study conducted by Meisel et al. on 28 patients who opted for undergoing level one microdisc surgery, autologous chondrocytes were isolated and cultured in in vitro and transplanted into the patients 3 months after the surgery and monitored their progress for the next 2 years, and it was found that the low back pain reduced gradually and the magnetic resonance imaging (MRI) T2 signal in NP cells also improved in treated and adjacent discs. Yoshikawa et al. administered autologous MSCs into the collagen sponge of two IVDD patients and it was noticed that their low back pain and radicular symptoms ameliorated within 2 years. In another study done by Orozco et al., they reported that 90% of participants among the 10 patients enrolled in the study who were suffering from chronic low back pain and degenerative disc disease recovered significantly after administration of autologous MSCs into their intradiscal space.
[Table 4] shows the published clinical trials targeting the regeneration of intervertebral disc.
|Table 4: Completed clinical studies on intervertebral discs regeneration using cell therapy|
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The results from the 12 ongoing clinical trials being conducted in the USA, European countries (Germany, Spain, Belgium, and Austria), and Korea are yet to be published in the online clinical trials database.
[Table 3] shows the registered clinical trials retrieved from the database available at clinical trials.gov on the treatment of IVDD with low back pain and the use of cell therapy.
| Conclusion|| |
Cell therapy is an attractive and appealing approach to regenerate the IVD, due to the slow and progressive nature of the degeneration that includes an increase in catabolic activity, resulting in the decreased matrix synthesis and cell senescence. The current knowledge specifies that cell therapy is safe although long-term results are unknown. Although much of the published animal data on the regenerative potential of injected chondrocyte or disc cells are promising for the regeneration of early IVDD, there are many questions that need to be answered regarding the timing of the treatment, optimal cell source, cell pretreatment, and cell carriers in humans. With the increasing number of clinical trials, cell therapy for IVD regeneration could bridge the disparity between aggressive surgical interventions and symptomatic care in some patients with IVD disease. A critical element for achieving natural tissue regeneration is to comprehensively understand the biological events required for the process of regeneration for each tissue and understand the IVD niche which is the major obstacle for regeneration of the IVD using cell therapy.
There are certain questions that need be answered or considered:
- Cell therapy mainly involves the implantation of one type of cells directly into the disc. Can the cells be implanted directly into the disc and differentiate into the desired populations required to regenerate a stable NP and repair the annulus fibrous layer and endplate?
- According to a study done by Brinjikji et al., 2015, many patients with severe disc degeneration are asymptomatic and not aware of having any spinal problems. Therefore, the question is whether pain should be the clinical target rather than IVDD itself?
- IVD niche is also an obstacle for successful regeneration using cell therapy. The major challenge is the survival and function of the injected cells in the IVD disc.
Hence, more clinical trials and better understanding should be our key for finding the best and amicable way for treating IVDD or at least ameliorate the IVDD in the best possible way for reconstruction and regeneration of the disc.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Pellisé F, Balagué F, Rajmil L, Cedraschi C, Aguirre M, Fontecha CG, et al.
Prevalence of low back pain and its effect on health-related quality of life in adolescents. Arch Pediatr Adolesc Med 2009;163:65-71.
Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, et al.
Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: A systematic analysis for the global burden of disease study 2010. Lancet 2012;380:2163-96.
Leung VY, Tam V, Chan D, Chan BP, Cheung KM. Tissue engineering for intervertebral disk degeneration. Orthop Clin North Am 2011;42:575-83, ix.
Roberts S, Menage J, Urban JP. Biochemical and structural properties of the cartilage end-plate and its relation to the intervertebral disc. Spine (Phila Pa 1976) 1989;14:166-74.
Smith LJ, Nerurkar NL, Choi KS, Harfe BD, Elliott DM. Degeneration and regeneration of the intervertebral disc: Lessons from development. Dis Model Mech 2011;4:31-41.
Vadalà G, Russo F, Di Martino A, Denaro V. Intervertebral disc regeneration: From the degenerative cascade to molecular therapy and tissue engineering. J Tissue Eng Regen Med 2015;9:679-90.
McCann MR, Séguin CA. Notochord cells in intervertebral disc development and degeneration. J Dev Biol 2016;4. pii: 3.
Yang Q, Xu HW, Hurday S, Xu BS. Construction strategy and progress of whole intervertebral disc tissue engineering. Orthop Surg 2016;8:11-8.
Thorpe AA, Sammon C, Le maitre C. ‘Cell or Not to Cell’ that is the question: For intervertebral disc regeneration? J Stem Cells Res Dev Ther 2015;2:1.
Lewis G. Nucleus pulposus replacement and regeneration/repair technologies: Present status and future prospects. J Biomed Mater Res B Appl Biomater 2012;100:1702-20.
Blau HM, Brazelton TR, Weimann JM. The evolving concept of a stem cell: Entity or function? Cell 2001;105:829-41.
Gou S, Oxentenko SC, Eldrige JS, Xiao L, Pingree MJ, Wang Z, et al.
Stem cell therapy for intervertebral disk regeneration. Am J Phys Med Rehabil 2014;93:S122-31.
Vadalà G, Russo F, Ambrosio L, Loppini M, Denaro V. Stem cells sources for intervertebral disc regeneration. World J Stem Cells 2016;8:185-201.
Sakai D, Schol J. Cell therapy for intervertebral disc repair: Clinical perspective. J Orthop Translat 2017;9:8-18.
Kregar Velikonja N, Urban J, Fröhlich M, Neidlinger-Wilke C, Kletsas D, Potocar U, et al.
Cell sources for nucleus pulposus regeneration. Eur Spine J 2014;23 Suppl 3:S364-74.
Tong W, Lu Z, Qin L, Mauck RL, Smith HE, Smith LJ, et al.
Cell therapy for the degenerating intervertebral disc. Transl Res 2017;181:49-58.
Ganey T, Libera J, Moos V, Alasevic O, Fritsch KG, Meisel HJ, et al.
Disc chondrocyte transplantation in a canine model: A treatment for degenerated or damaged intervertebral disc. Spine (Phila Pa 1976) 2003;28:2609-20.
Park JB, Chang H, Kim KW. Expression of fas ligand and apoptosis of disc cells in herniated lumbar disc tissue. Spine (Phila Pa 1976) 2001;26:618-21.
Takada T, Nishida K, Doita M, Kurosaka M. Fas ligand exists on intervertebral disc cells: A potential molecular mechanism for immune privilege of the disc. Spine (Phila Pa 1976) 2002;27:1526-30.
Pennicooke B, Moriguchi Y, Hussain I, Bonssar L, Härtl R. Biological treatment approaches for degenerative disc disease: A Review of clinical trials and future directions. Cureus 2016;8:e892.
Meisel HJ, Siodla V, Ganey T, Minkus Y, Hutton WC, Alasevic OJ, et al.
Clinical experience in cell-based therapeutics: Disc chondrocyte transplantation A treatment for degenerated or damaged intervertebral disc. Biomol Eng 2007;24:5-21.
Nomura T, Mochida J, Okuma M, Nishimura K, Sakabe K. Nucleus pulposus allograft retards intervertebral disc degeneration. Clin Orthop Relat Res 2001;389:94-101.
Hohaus C, Ganey TM, Minkus Y, Meisel HJ. Cell transplantation in lumbar spine disc degeneration disease. Eur Spine J 2008;17 Suppl 4:492-503.
Gruber HE, Johnson TL, Leslie K, Ingram JA, Martin D, Hoelscher G, et al.
Autologous intervertebral disc cell implantation: A model using Psammomys obesus
, the sand rat. Spine (Phila Pa 1976) 2002;27:1626-33.
Zhang Y, Chee A, Shi P, Wang R, Moss I, Chen EY, et al.
Allogeneic articular chondrocyte transplantation downregulates interleukin 8 gene expression in the degenerating rabbit intervertebral disk in vivo
. Am J Phys Med Rehabil 2015;94:530-8.
Moriguchi Y, Alimi M, Khair T, Manolarakis G, Berlin C, Bonassar LJ, et al.
Biological treatment approaches for degenerative disk disease: A Literature review of in vivo
animal and clinical data. Global Spine J 2016;6:497-518.
Wei A, Shen B, Williams L, Diwan A. Mesenchymal stem cells: Potential application in intervertebral disc regeneration. Transl Pediatr 2014;3:71-90.
Risbud MV, Albert TJ, Guttapalli A, Vresilovic EJ, Hillibrand AS, Vaccaro AR, et al.
Differentiation of mesenchymal stem cells towards a nucleus pulposus-like phenotype in vitro
: Implications for cell-based transplantation therapy. Spine (Phila Pa 1976) 2004;29:2627-32.
Wei A, Tao H, Chung SA, Brisby H, Ma DD, Diwan AD, et al.
The fate of transplanted xenogeneic bone marrow-derived stem cells in rat intervertebral discs. J Orthop Res 2009;27:374-9.
Okuma M, Mochida J, Nishimura K, Sakabe K, Seiki K. Reinsertion of stimulated nucleus pulposus cells retards intervertebral disc degeneration: An in vitro
and in vivo
experimental study. J Orthop Res 2000;18:988-97.
Watanabe K, Mochida J, Nomura T, Okuma M, Sakabe K, Seiki K, et al.
Effect of reinsertion of activated nucleus pulposus on disc degeneration: An experimental study on various types of collagen in degenerative discs. Connect Tissue Res 2003;44:104-8.
Zhang YG, Guo X, Xu P, Kang LL, Li J. Bone mesenchymal stem cells transplanted into rabbit intervertebral discs can increase proteoglycans. Clin Orthop Relat Res 2005;430:219-26.
Iwashina T, Mochida J, Sakai D, Yamamoto Y, Miyazaki T, Ando K, et al.
Feasibility of using a human nucleus pulposus cell line as a cell source in cell transplantation therapy for intervertebral disc degeneration. Spine (Phila Pa 1976) 2006;31:1177-86.
Ho G, Leung VY, Cheung KM, Chan D. Effect of severity of intervertebral disc injury on mesenchymal stem cell-based regeneration. Connect Tissue Res 2008;49:15-21.
Hiyama A, Mochida J, Iwashina T, Omi H, Watanabe T, Serigano K, et al.
Transplantation of mesenchymal stem cells in a canine disc degeneration model. J Orthop Res 2008;26:589-600.
Sobajima S, Vadala G, Shimer A, Kim JS, Gilbertson LG, Kang JD, et al.
Feasibility of a stem cell therapy for intervertebral disc degeneration. Spine J 2008;8:888-96.
Murrell W, Sanford E, Anderberg L, Cavanagh B, Mackay-Sim A. Olfactory stem cells can be induced to express chondrogenic phenotype in a rat intervertebral disc injury model. Spine J 2009;9:585-94.
Jeong JH, Jin ES, Min JK, Jeon SR, Park CS, Kim HS, et al.
Human mesenchymal stem cells implantation into the degenerated coccygeal disc of the rat. Cytotechnology 2009;59:55-64.
Hee HT, Ismail HD, Lim CT, Goh JC, Wong HK. Effects of implantation of bone marrow mesenchymal stem cells, disc distraction and combined therapy on reversing degeneration of the intervertebral disc. J Bone Joint Surg Br 2010;92:726-36.
Jeong JH, Lee JH, Jin ES, Min JK, Jeon SR, Choi KH, et al.
Regeneration of intervertebral discs in a rat disc degeneration model by implanted adipose-tissue-derived stromal cells. Acta Neurochir (Wien) 2010;152:1771-7.
Miyamoto T, Muneta T, Tabuchi T, Matsumoto K, Saito H, Tsuji K, et al
. Intradiscal transplantation of synovial mesenchymal stem cells prevents intervertebral disc degeneration through suppression of matrix metalloproteinase-related genes in nucleus pulposus cells in rabbits. Arthritis Res Ther 2010;12:R206.
Serigano K, Sakai D, Hiyama A, Tamura F, Tanaka M, Mochida J, et al.
Effect of cell number on mesenchymal stem cell transplantation in a canine disc degeneration model. J Orthop Res 2010;28:1267-75.
Feng G, Zhao X, Liu H, Zhang H, Chen X, Shi R, et al.
Transplantation of mesenchymal stem cells and nucleus pulposus cells in a degenerative disc model in rabbits: A comparison of 2 cell types as potential candidates for disc regeneration. J Neurosurg Spine 2011;14:322-9.
Prologo JD, Pirasteh A, Tenley N, Yuan L, Corn D, Hart D, et al.
Percutaneous image-guided delivery for the transplantation of mesenchymal stem cells in the setting of degenerated intervertebral discs. J Vasc Interv Radiol 2012;23:1084-8.e6.
Vadalà G, Sowa G, Hubert M, Gilbertson LG, Denaro V, Kang JD, et al.
Mesenchymal stem cells injection in degenerated intervertebral disc: Cell leakage may induce osteophyte formation. J Tissue Eng Regen Med 2012;6:348-55.
Yi Z, Guanjun T, Lin C, Zifeng P. Effects of transplantation of hTIMP-1-expressing bone marrow mesenchymal stem cells on the extracellular matrix of degenerative intervertebral discs in an in vivo
rabbit model. Spine (Phila Pa 1976) 2014;39:E669-75.
Cai F, Wu XT, Xie XH, Wang F, Hong X, Zhuang SY, et al.
Evaluation of intervertebral disc regeneration with implantation of bone marrow mesenchymal stem cells (BMSCs) using quantitative T2 mapping: A study in rabbits. Int Orthop 2015;39:149-59.
Tam V, Rogers I, Chan D, Leung VY, Cheung KM. A comparison of intravenous and intradiscal delivery of multipotential stem cells on the healing of injured intervertebral disk. J Orthop Res 2014;32:819-25.
Sakai D, Mochida J, Iwashina T, Watanabe T, Nakai T, Ando K, et al.
Differentiation of mesenchymal stem cells transplanted to a rabbit degenerative disc model: Potential and limitations for stem cell therapy in disc regeneration. Spine (Phila Pa 1976) 2005;30:2379-87.
Cao C, Zou J, Liu X, Shapiro A, Moral M, Luo Z, et al.
Bone marrow mesenchymal stem cells slow intervertebral disc degeneration through the NF-κB pathway. Spine J 2015;15:530-8.
Elabd C, Centeno CJ, Schultz JR, Lutz G, Ichim T, Silva FJ, et al.
Intra-discal injection of autologous, hypoxic cultured bone marrow-derived mesenchymal stem cells in five patients with chronic lower back pain: A long-term safety and feasibility study. J Transl Med 2016;14:253.
Vasiliadis ES, Pneumaticos SG, Evangelopoulos DS, Papavassiliou AG. Biologic treatment of mild and moderate intervertebral disc degeneration. Mol Med 2014;20:400-9.
Zhang Y, An HS, Tannoury C, Thonar EJ, Freedman MK, Anderson DG, et al.
Biological treatment for degenerative disc disease: Implications for the field of physical medicine and rehabilitation. Am J Phys Med Rehabil 2008;87:694-702.
Bertram H, Kroeber M, Wang H, Unglaub F, Guehring T, Carstens C, et al.
Matrix-assisted cell transfer for intervertebral disc cell therapy. Biochem Biophys Res Commun 2005;331:1185-92.
Maldonado BA, Oegema TR Jr. Initial characterization of the metabolism of intervertebral disc cells encapsulated in microspheres. J Orthop Res 1992;10:677-90.
Chiba K, Andersson GB, Masuda K, Thonar EJ. Metabolism of the extracellular matrix formed by intervertebral disc cells cultured in alginate. Spine (Phila Pa 1976) 1997;22:2885-93.
Collin EC, Grad S, Zeugolis DI, Vinatier CS, Clouet JR, Guicheux JJ, et al.
An injectable vehicle for nucleus pulposus cell-based therapy. Biomaterials 2011;32:2862-70.
Ifkovits JL, Burdick JA. Review: Photopolymerizable and degradable biomaterials for tissue engineering applications. Tissue Eng 2007;13:2369-85.
Sato M, Asazuma T, Ishihara M, Ishihara M, Kikuchi T, Kikuchi M, et al.
An experimental study of the regeneration of the intervertebral disc with an allograft of cultured annulus fibrosus cells using a tissue-engineering method. Spine (Phila Pa 1976) 2003;28:548-53.
Sakai D, Mochida J, Yamamoto Y, Nomura T, Okuma M, Nishimura K, et al.
Transplantation of mesenchymal stem cells embedded in atelocollagen gel to the intervertebral disc: A potential therapeutic model for disc degeneration. Biomaterials 2003;24:3531-41.
Crevensten G, Walsh AJ, Ananthakrishnan D, Page P, Wahba GM, Lotz JC, et al.
Intervertebral disc cell therapy for regeneration: Mesenchymal stem cell implantation in rat intervertebral discs. Ann Biomed Eng 2004;32:430-4.
Sakai D, Mochida J, Iwashina T, Hiyama A, Omi H, Imai M, et al.
Regenerative effects of transplanting mesenchymal stem cells embedded in atelocollagen to the degenerated intervertebral disc. Biomaterials 2006;27:335-45.
Ganey T, Hutton WC, Moseley T, Hedrick M, Meisel HJ. Intervertebral disc repair using adipose tissue-derived stem and regenerative cells: Experiments in a canine model. Spine (Phila Pa 1976) 2009;34:2297-304.
Henriksson HB, Svanvik T, Jonsson M, Hagman M, Horn M, Lindahl A, et al.
Transplantation of human mesenchymal stems cells into intervertebral discs in a xenogeneic porcine model. Spine (Phila Pa 1976) 2009;34:141-8.
Ruan DK, Xin H, Zhang C, Wang C, Xu C, Li C, et al.
Experimental intervertebral disc regeneration with tissue-engineered composite in a canine model. Tissue Eng Part A 2010;16:2381-9.
Allon AA, Aurouer N, Yoo BB, Liebenberg EC, Buser Z, Lotz JC, et al.
Structured coculture of stem cells and disc cells prevent disc degeneration in a rat model. Spine J 2010;10:1089-97.
Omlor GW, Bertram H, Kleinschmidt K, Fischer J, Brohm K, Guehring T, et al.
Methods to monitor distribution and metabolic activity of mesenchymal stem cells following in vivo
injection into nucleotomized porcine intervertebral discs. Eur Spine J 2010;19:601-12.
Yang H, Wu J, Liu J, Ebraheim M, Castillo S, Liu X, et al.
Transplanted mesenchymal stem cells with pure fibrinous gelatin-transforming growth factor-beta1 decrease rabbit intervertebral disc degeneration. Spine J 2010;10:802-10.
Huang B, Zhuang Y, Li CQ, Liu LT, Zhou Y. Regeneration of the intervertebral disc with nucleus pulposus cell-seeded collagen II/hyaluronan/chondroitin-6-sulfate tri-copolymer constructs in a rabbit disc degeneration model. Spine (Phila Pa 1976) 2011;36:2252-9.
Bendtsen M, Bünger CE, Zou X, Foldager C, Jørgensen HS. Autologous stem cell therapy maintains vertebral blood flow and contrast diffusion through the endplate in experimental intervertebral disc degeneration. Spine (Phila Pa 1976) 2011;36:E373-9.
Zhang Y, Drapeau S, Howard SA, Thonar EJ, Anderson DG. Transplantation of goat bone marrow stromal cells to the degenerating intervertebral disc in a goat disc injury model. Spine (Phila Pa 1976) 2011;36:372-7.
Chun HJ, Kim YS, Kim BK, Kim EH, Kim JH, Do BR, et al.
Transplantation of human adipose-derived stem cells in a rabbit model of traumatic degeneration of lumbar discs. World Neurosurg 2012;78:364-71.
Ghosh P, Moore R, Vernon-Roberts B, Goldschlager T, Pascoe D, Zannettino A, et al.
Immunoselected STRO-3+ mesenchymal precursor cells and restoration of the extracellular matrix of degenerate intervertebral discs. J Neurosurg Spine 2012;16:479-88.
Henriksson HB, Hagman M, Horn M, Lindahl A, Brisby H. Investigation of different cell types and gel carriers for cell-based intervertebral disc therapy, in vitro
and in vivo
studies. J Tissue Eng Regen Med 2012;6:738-47.
Barczewska M, Wojtkiewicz J, Habich A, Janowski M, Adamiak Z, Holak P, et al.
MR monitoring of minimally invasive delivery of mesenchymal stem cells into the porcine intervertebral disc. PLoS One 2013;8:e74658.
Leckie SK, Sowa GA, Bechara BP, Hartman RA, Coelho JP, Witt WT, et al.
Injection of human umbilical tissue-derived cells into the nucleus pulposus alters the course of intervertebral disc degeneration in vivo
. Spine J 2013;13:263-72.
Li YY, Diao HJ, Chik TK, Chow CT, An XM, Leung V, et al.
Delivering mesenchymal stem cells in collagen microsphere carriers to rabbit degenerative disc: Reduced risk of osteophyte formation. Tissue Eng Part A 2014;20:1379-91.
Wang H, Zhou Y, Huang B, Liu LT, Liu MH, Wang J, et al.
Utilization of stem cells in alginate for nucleus pulposus tissue engineering. Tissue Eng Part A 2014;20:908-20.
Subhan RA, Puvanan K, Murali MR, Raghavendran HR, Shani S, Abdullah BJ, et al.
Fluoroscopy assisted minimally invasive transplantation of allogenic mesenchymal stromal cells embedded in hyStem reduces the progression of nucleus pulposus degeneration in the damaged intervertebral [corrected] disc: A preliminary study in rabbits. ScientificWorldJournal 2014;2014:818502.
Haufe SM, Mork AR. Intradiscal injection of hematopoietic stem cells in an attempt to rejuvenate the intervertebral discs. Stem Cells Dev 2006;15:136-7.
Meisel HJ, Ganey T, Hutton WC, Libera J, Minkus Y, Alasevic O, et al.
Clinical experience in cell-based therapeutics: Intervention and outcome. Eur Spine J 2006;15 Suppl 3:S397-405.
Yoshikawa T, Ueda Y, Miyazaki K, Koizumi M, Takakura Y. Disc regeneration therapy using marrow mesenchymal cell transplantation: A report of two case studies. Spine (Phila Pa 1976) 2010;35:E475-80.
Orozco L, Soler R, Morera C, Alberca M, Sánchez A, García-Sancho J, et al.
Intervertebral disc repair by autologous mesenchymal bone marrow cells: A pilot study. Transplantation 2011;92:822-8.
Coric D, Pettine K, Sumich A, Boltes MO. Prospective study of disc repair with allogeneic chondrocytes presented at the 2012 joint spine section meeting. J Neurosurg Spine 2013;18:85-95.
Pettine KA, Murphy MB, Suzuki RK, Sand TT. Percutaneous injection of autologous bone marrow concentrate cells significantly reduces lumbar discogenic pain through 12 months. Stem Cells 2015;33:146-56.
Mochida J, Sakai D, Nakamura Y, Watanabe T, Yamamoto Y, Kato S, et al.
Intervertebral disc repair with activated nucleus pulposus cell transplantation: A three-year, prospective clinical study of its safety. Eur Cell Mater 2015;29:202-12.
Brinjikji W, Luetmer PH, Comstock B, Bresnahan BW, Chen LE, Deyo RA, et al.
Systematic literature review of imaging features of spinal degeneration in asymptomatic populations. AJNR Am J Neuroradiol 2015;36:811-6.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]